It is generally accepted that TGFbeta is both a tumor suppressor and a tumor promoter. While loss or attenuation of TGFbet signal transduction is permissive for transformation, introduction of dominant negative TGFbeta receptors into metastatic cancer cells has been shown to inhibit epithelial to mesenchymal transition (EMT), motility, invasiveness, survival, and metastases. In addition, there is evidence that excess production and/or activation of TGFbeta by cancer cells can contribute to tumor progression by paracrine mechanisms involving neo-angiogenesis, production of stroma and proteases, and subversion of immune surveillance mechanisms in tumor hosts. These data provide a rationale in favor of blockade of autocrine/paracrine TGFbeta signaling in human tumors with a therapeutic intent. Several treatment approaches are currently in early clinical development and have been the focus of our laboratory during the last funding period. Many questions remain about the viability of an anti- TGFbeta treatment strategy, the best molecular approach for inhibition of TGFbeta function in vivo, the biochemical surrogate markers of tumor response, the molecular profiles in tumors for selection into clinical trials, potential toxicities, to mention a few. Therefore, in order to address these issues, we propose the following research aims in this competing renewal: Specific Aim 1: To determine if conditional deletion of TbetaRII in mammary cancer cells in vitro and in vivo inhibits autocrine TGFbeta signaling and tumor progression. Specific Aim 2: To determine whether therapeutic inhibitors of TGFbeta abrogate TGFbeta signaling and induce an antitumor effect both in vitro and in vivo. Specific Aim 3: To determine whether TGFbeta transactivates erbB receptors and elucidate if this transactivation involves cleavage of erbB receptor trans-membrane ligands. Specific Aim 4: To determine if the activated type I TGFbeta receptor (Alk5) synergizes with HER2 (erbB2) in mammary tumorigenesis and whether it negates the therapeutic effect of HER2 inhibitors in vivo.